The management and outcome of hyponatraemia following transsphenoidal surgery: a retrospective observational study.

PURPOSE: Hyponatraemia is a common complication following transsphenoidal surgery. However, there is sparse data on its optimal management and impact on clinical outcomes. The aim of this study was to evaluate the management and outcome of hyponatraemia following transsphenoidal surgery. METHODS: A prospectively maintained database was searched over a 4-year period between January 2016 and December 2019, to identify all patients undergoing transsphenoidal surgery. A retrospective case-note review was performed to extract data on hyponatraemia management and outcome. RESULTS: Hyponatraemia occurred in 162 patients (162/670; 24.2%) with a median age of 56 years. Female gender and younger age were associated with hyponatraemia, with mean nadir sodium being 128.6 mmol/L on postoperative day 7. Hyponatraemic patients had longer hospital stay than normonatraemic group with nadir sodium being inversely associated with length of stay (p < 0.001). In patients with serum sodium ≤ 132 mmol/L, syndrome of inappropriate antidiuretic hormone secretion (SIADH) was the commonest cause (80/111; 72%). Among 76 patients treated with fluid restriction as a monotherapy, 25 patients (25/76; 32.9%) did not achieve a rise in sodium after 3 days of treatment. Readmission with hyponatraemia occurred in 11 cases (11/162; 6.8%) at a median interval of 9 days after operation. CONCLUSION: Hyponatraemia is a relatively common occurrence following transsphenoidal surgery, is associated with longer hospital stay and risk of readmission and the effectiveness of fluid restriction is limited. These findings highlight the need for further studies to better identify and treat high-risk patients, including the use of arginine vasopressin receptor antagonists.

Temporal trends in craniopharyngioma management and long-term endocrine outcomes: A multicentre cross-sectional study.

BACKGROUND: The optimal management of craniopharyngiomas remains controversial. OBJECTIVES: To examine temporal trends in the management of craniopharyngioma with a focus on endocrine outcomes. METHODS: This was a cross-sectional, multicentre study. Patients treated between 1951 and 2015 were identified and divided into four quartiles. Demographics, presentation, treatment and outcomes were collected. RESULTS: In total, 142 patients with childhood-onset craniopharyngioma (48/142; 34%) and adult-onset disease (94/142; 66%) were included. The median follow-up was 15 years (IQR 5-23 years). Across quartiles, there was a significant trend towards using transsphenoidal surgery (P < .0001). The overall use of radiotherapy was not different among the four quartiles (P = .33). At the latest clinical review, the incidence of GH, ACTH, gonadotrophin deficiencies and anterior panhypopituitarism fell significantly across the duration of the study. Anterior panhypopituitarism was not affected by treatment modality (surgery vs surgery and radiotherapy) (P = .23). There was no difference in the incidence of high BMI (≥25 kg/m2 ) among the four quartiles (P = .14). BMI was higher in patients who treated with surgery and radiotherapy than those treated with surgery only (P = .006). Tumour regrowth occurred in 51 patients (51/142; 36%) with no difference in regrowth among quartiles over the time course of the study (P = .15). CONCLUSION: We demonstrate a significant reduction in panhypopituitarism in craniopharyngioma patients over time, most likely because of a trend towards more transsphenoidal surgery. However, long-term endocrine sequelae remain common and lifelong follow-up is required.

Time above the MIC of Piperacillin-Tazobactam as a Predictor of Outcome in Pseudomonas aeruginosa Bacteremia.

Pseudomonas aeruginosa bacteremia is an infection associated with a high mortality rate. Piperacillin-tazobactam is a ß-lactam-ß-lactamase inhibitor combination that is frequently used for the management of Pseudomonas aeruginosa infections. The pharmacokinetic-pharmacodynamic index associated with in vitro maximal bacterial killing for piperacillin-tazobactam is the percentage of the time between doses at which the free fraction concentration remains above the MIC (%fT >MIC). However, the precise %fT >MIC target associated with improved clinical outcomes is unknown. The aim of this study was to investigate the correlation between the survival of patients with Pseudomonas aeruginosa bacteremia and the threshold of the piperacillin-tazobactam %fT >MIC This retrospective study included all adult patients hospitalized over an 82-month period with Pseudomonas aeruginosa bacteremia and treated with piperacillin-tazobactam. Patients with a polymicrobial infection or those who died within 72 h of the time of collection of a sample for culture were excluded. The %fT >MIC of piperacillin-tazobactam associated with in-hospital survival was derived using classification and regression tree analysis. After screening 270 patients, 78 were eligible for inclusion in the study; 18% died during hospitalization. Classification and regression tree analysis identified a %fT >MIC of >60.68% to be associated with improved survival, and this remained statistically significant after controlling for clinical covariates (odds ratio = 7.74, 95% confidence interval = 1.32 to 45.2). In conclusion, the findings recommend dosing of piperacillin-tazobactam with the aim of achieving a pharmacodynamic target %fT >MIC of at least 60% in these patients.

Changes in perampanel levels during de-induction: Simulations following carbamazepine discontinuation.

OBJECTIVE: To evaluate the time course of changes in perampanel levels when co-administered with carbamazepine, and following carbamazepine discontinuation, using a physiologically based pharmacokinetic (PBPK) model. METHODS: The PBPK model was developed, verified using clinical PK data, and used to simulate the effect of abrupt discontinuation and down-titration (75 mg twice daily [bid]/wk) of co-administered carbamazepine 300 mg bid on the PK of perampanel once daily (qd). Perampanel dose tapering (8-4 mg) and up-titration (2-6 mg) were simulated during abrupt carbamazepine 300 mg bid discontinuation to identify a titration schedule that minimizes changes in perampanel plasma concentrations. RESULTS: The PBPK model accurately reproduced perampanel plasma concentration-time profiles from clinical studies in single- and multiple-dose regimen simulations, including multiple-dose carbamazepine co-administration. The time course of return to pre-induced perampanel levels occurred more slowly following carbamazepine down-titration (~48 days after first down-titration) vs abrupt discontinuation (~25 days). Perampanel dose tapering (8-4 mg) at abrupt carbamazepine discontinuation produced minimal changes in steady-state concentrations, which returned to the levels observed during carbamazepine co-administration in ~15 days from the time of carbamazepine discontinuation. When perampanel was up-titrated in the presence of carbamazepine, return to steady state occurred more slowly when carbamazepine was down-titrated weekly (~45 days) vs abrupt discontinuation (~24 days). CONCLUSION: This PBPK model simulated and predicted optimal perampanel dose tapering and up-titration schedules for maintaining perampanel levels during conversion to monotherapy. These results may guide physicians when managing conversion from perampanel polytherapy with concomitant enzyme-inducing anti-seizure medications to monotherapy.

Rathke's cleft cysts following transsphenoidal surgery: long-term outcomes and development of an optimal follow-up strategy.

BACKGROUND: In patients with symptomatic Rathke's cleft cyst, transsphenoidal surgery is highly effective at preventing further visual loss and usually allows for some recovery of vision. However, cyst recurrence and the need for re-operation are well recognized. To this end, the aim of this study was to investigate patterns of recurrence and long-term outcomes and to use this information to develop an optimal follow-up strategy. METHOD: A prospectively maintained database was searched over a 10-year period between 1 January 2008 and the 1 January 2018 to identify all adults that underwent transsphenoidal surgery with a new diagnosis of Rathke's cleft cyst. A retrospective case note review was performed for each patient to extract data on their presentation, investigation, treatment, and outcome. RESULTS: In all, 61 eligible patients were identified. The median follow-up was 34 months (range 2-112 months). In the 22 patients with pre-operative visual loss, the outcomes at 6 months were as follows: normal vision (2/22; 9.1%), improved but not normal (7/22; 31.8%), stable (12/22; 54.5%), worse but not blind (1/22; 4.5%), and blind (0/22; 0%). The overall rate of regrowth and re-operation in our study was 19.7 and 11.5%, respectively. The only factor that was significantly associated with recurrence was the presence of residual cystic disease on the post-operative MRI (p < 0.001). CONCLUSIONS: We propose a follow-up strategy that stratifies patients at "low risk" if there is no residual cyst, with increasing interval scans, or "high risk" if there is residual cyst, with annual visual assessment and scans.

Impact of perampanel on pharmacokinetics of concomitant antiepileptics in patients with partial-onset seizures: pooled analysis of clinical trials.

AIMS: To evaluate the impact of perampanel and demographics on clearance of concomitant antiepileptic drugs (AEDs), in patients with refractory partial-onset seizures. METHODS: Pooled data from three Phase III clinical studies with adjunctive perampanel were used. Blood samples for evaluation of 11 concomitant AEDs were taken during baseline (before perampanel initiation), and at weeks 10, 14, and 19 during the maintenance phase of perampanel treatment (2-12 mg/day, once daily at bedtime). Models estimating apparent clearance of each concomitant AED were fitted to the data, and the effects of perampanel and demographic variables on clearance were determined. Final models were assessed with goodness of fit plots including population predictions and individual predictions against observations. RESULTS: No significant impact of perampanel on clearance was found for clonazepam (n = 81), levetiracetam (n = 330), phenobarbital (n = 54), phenytoin (n = 90), topiramate (n = 226) or zonisamide (n = 93). Statistically significant, but small and not clinically relevant increases in model-predicted clearance were detected for carbamazepine (+4.3% with 12 mg perampanel; n = 379), clobazam (+3.4% males, +7.7% females, 12 mg; n = 114), lamotrigine (+9.3%, 12 mg; n = 356), and valproic acid (+5.0%, 12 mg; n = 349). Oxcarbazepine clearance was reduced (26%; n = 200), but the clinical relevance is unclear as levels of the active metabolite (the monohydroxy derivative of oxcarbazepine) were not measured. CONCLUSIONS: Population PK data show that perampanel (2-12 mg/day, once daily at bedtime) has no relevant impact on the clearance of the most commonly used concomitant AEDs.

Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer.

AIMS: Lenvatinib was recently approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Here, we characterized the pharmacokinetic (PK) profile of lenvatinib and identified intrinsic and extrinsic factors that explain interindividual PK variability in humans. METHODS: This population PK analysis used pooled data from 15 clinical studies, including eight phase 1 studies in healthy subjects, four phase 1 studies in patients with solid tumours, two phase 2 studies in patients with thyroid cancer and one phase 3 study in patients with RR-DTC. RESULTS: The final pooled dataset included data from 779 subjects receiving 3.2-32 mg oral lenvatinib, mainly once daily as tablets or capsules. Lenvatinib PK was best described by a three-compartment model with linear elimination. Lenvatinib absorption was best described by simultaneous first- and zero-order absorption. The population mean value for lenvatinib apparent clearance (CL/F) was 6.56 l h(-1) [percent coefficient of variation (%CV) 25.5], and was independent of dose and time. The relative bioavailability of lenvatinib in capsule form was 90% vs. tablets (%CV 30.2). The final PK model included significant but marginal effects of body weight (2.8% of CL/F variation), liver-function markers [alkaline phosphatase (-11.7%) and albumin (-6.3%)] and concomitant cytochrome P450 3A4 inducers (+30%) and inhibitors (-7.8%) on lenvatinib CL/F. Lenvatinib PK was unaffected by pH-elevating agents, dose, age, sex, race, alanine aminotransferase, aspartate aminotransferase or bilirubin levels, or renal function. CONCLUSIONS: The significant effects of several covariates on lenvatinib PK variability were small in magnitude, and therefore were not considered clinically relevant, or to warrant any dose adjustment.

The practical impact of altered dosing on perampanel plasma concentrations: pharmacokinetic modeling from clinical studies.

RATIONALE: Perampanel is a selective AMPA receptor antagonist approved for adjunctive therapy in patients with refractory partial-onset seizures. Perampanel is metabolized primarily via CYP3A4, yet it has a relatively long half-life of 105h; it is, therefore, recommended that perampanel be given once daily (preferably at bedtime). Many patients occasionally have less-than-perfect adherence to their drug regimen, and given the known pharmacokinetic interactions of perampanel with commonly used enzyme-inducing antiepileptic drugs (EIAEDs), we explored the effects of a missed dose on steady-state perampanel plasma concentrations and the ramifications of "make up" doses in these patients. Although perampanel is approved for once-daily dosing, some clinicians may elect to give perampanel as a divided dose (i.e., twice daily), so we also sought to examine the pharmacokinetic impact of twice- versus once-daily dosing. METHODS: Pharmacokinetic simulations were performed using validated perampanel pharmacokinetic parameters, derived from 19 phase I studies in 606 subjects, to investigate the effect on perampanel plasma concentration of (1) missing a dose of perampanel followed by delayed replacement of the missed dose, (2) missing a dose followed by resumption of scheduled therapy, and (3) missing a dose in the presence/absence of carbamazepine. Simulations were done for a typical patient receiving an 8-mg once-daily or a 4-mg twice-daily dose using the nonlinear mixed effects program, NONMEM v7.2, in conjunction with PDx-pop v5. RESULTS: Our results corroborate that given the pharmacokinetic characteristics of perampanel, a missed dose is unlikely to cause as much fluctuation in plasma concentration as would be expected for a drug with a short half-life. Importantly, simulations suggest that supplementing a missed dose 6-12h later, followed by continuation of the regular schedule, may not result in any significant "spikes" in perampanel plasma concentrations. Simulations demonstrated that twice-daily dosing offered little advantage in further flattening the concentration-time profile of perampanel in the adherent patient. However, fluctuations in plasma concentrations are minimized by twice-daily dosing in patients receiving concomitant EIAEDs. CONCLUSIONS: These pharmacokinetic simulations suggest that the long half-life of perampanel may be advantageous in conferring a relatively smooth concentration-time profile with a once-daily or twice-daily dosing, even in the presence of concomitant EIAEDs. However, the results of the present study suggest that perampanel replacement is recommended for patients taking an EIAED to mitigate the potential risks associated with reduced exposure. Confirmation of the ultimate clinical impact of these findings will require further study.

Machine Learning Analysis of Post-Operative Tumour Progression in Non-Functioning Pituitary Neuroendocrine Tumours: A Pilot Study.

Post-operative tumour progression in patients with non-functioning pituitary neuroendocrine tumours is variable. The aim of this study was to use machine learning (ML) models to improve the prediction of post-operative outcomes in patients with NF PitNET. We studied data from 383 patients who underwent surgery with or without radiotherapy, with a follow-up period between 6 months and 15 years. ML models, including k-nearest neighbour (KNN), support vector machine (SVM), and decision tree, showed superior performance in predicting tumour progression when compared with parametric statistical modelling using logistic regression, with SVM achieving the highest performance. The strongest predictor of tumour progression was the extent of surgical resection, with patient age, tumour volume, and the use of radiotherapy also showing influence. No features showed an association with tumour recurrence following a complete resection. In conclusion, this study demonstrates the potential of ML models in predicting post-operative outcomes for patients with NF PitNET. Future work should look to include additional, more granular, multicentre data, including incorporating imaging and operative video data.

Population pharmacokinetic-pharmacodynamic modeling of serum biomarkers as predictors of tumor dynamics following lenvatinib treatment in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC).

Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptor-α (PDGFRα), KIT, and RET that have been implicated in pathogenic angiogenesis, tumor growth, and cancer. The primary objective of this work was to evaluate, by establishing quantitative relationships, whether lenvatinib exposure and longitudinal serum biomarker data (VEGF, Ang-2, Tie-2, and FGF-23) are predictors for change in longitudinal tumor size which was assessed based on data from 558 patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving either lenvatinib or placebo treatment. Lenvatinib PK was best described by a 3-compartment model with simultaneous first- and zero-order absorption and linear elimination from the central compartment with significant covariates (body weight, albumin <30 g/dL, ALP>ULN, RR-DTC, RCC, HCC subjects, and concomitant CYP3A inhibitors). Except for body weight, none of the covariates have any clinically meaningful effect on exposure to lenvatinib. Longitudinal biomarker measurements over time were reasonably well defined by a PK/PD model with common EC50, Emax, and a slope for disease progression for all biomarkers. Longitudinal tumor measurements over time were reasonably well defined by a tumor growth inhibition Emax model, which in addition to lenvatinib exposure, included model-predicted relative changes from baseline over time for Tie-2 and Ang-2 as having significant association with tumor response. The developed PK/PD models pave the way for dose optimization and potential prediction of clinical response.

Concentration-effect relationships with perampanel in patients with pharmacoresistant partial-onset seizures.

PURPOSE: Although there is a general paucity of published pharmacokinetic (PK) data for new antiepileptic drugs (AEDs), PK analyses of pooled data from clinical studies of perampanel have recently been presented. We present PK/pharmacodynamic (PD) analyses of pooled data from phase III studies of perampanel describing efficacy and safety as a function of exposure, in order to determine whether a predictable concentration-effect relationship exists for perampanel efficacy and/or adverse events (AEs). The effects of concomitant enzyme-inducing AEDs (EIAEDs) and non-enzyme-inducing AEDs on the exposure, efficacy, and safety of perampanel are also considered. METHODS: Three multicenter, randomized, double-blind, placebo-controlled phase III studies investigated the efficacy and safety of perampanel 2-12 mg in patients with uncontrolled partial-onset seizures despite prior therapy with two or more AEDs. From baseline onward, patients also received ongoing treatment with stable doses of one to three approved concomitant AEDs. AEs were monitored throughout the studies. Changes from baseline in seizure frequency and 50% responder rates were evaluated. Exposure to perampanel was predicted based on the actual (last) dose using a previously established PK model. A population PK/PD model for the relationship between perampanel exposure and seizure frequency was estimated using nonlinear mixed-effect modeling with first-order conditional estimation, whereas logistic analyses for responder rate and AEs were performed using SAS analysis software. KEY FINDINGS: The PK/PD population included 1,109 patients. Seizure frequency decreased linearly as predicted perampanel average steady-state plasma concentrations increased. Concomitant EIAEDs (carbamazepine, oxcarbazepine, and phenytoin) reduced exposure to perampanel but had no effect on the slope of the PD model-predicted relationship between exposure and reduction in seizure frequency. The probability of patients achieving a response was predicted to increase as perampanel average plasma concentration at steady state increased. No demographic, AED, region, or study covariate had any effect on the probability of achieving a positive treatment response to perampanel or on the slope of the exposure-response curve. Across the phase III studies, there were reports of dizziness (32.9%), somnolence (21.7%), fatigue (13.9%), irritability (12.3%), gait disturbance (9.1%), weight increase (6.1%), dysarthria (4.5%), and euphoric mood (0.5%); the model-predicted probability of these AEs increased significantly at higher exposure to perampanel (all p < 0.001). There was no effect of demographic variables or region on the probability of experiencing any of the AEs analyzed. SIGNIFICANCE: PK and PD analyses have played a pivotal role in the clinical development of perampanel as an adjunctive treatment for pharmacoresistant partial-onset seizures. Phase III data suggest that a significant relationship exists between increases in perampanel plasma concentration (i.e., systemic exposure) and reductions in seizure frequency. In addition, increases in perampanel plasma concentration may potentially be associated with increases in AE rates. The model-predicted concentration-safety profile of perampanel does not appear to be affected by patient age, gender, or ethnicity. Although concomitant EIAEDs may influence perampanel PK, they do not appear to alter the relationship between perampanel plasma concentration and seizure frequency. Understanding these relationships between perampanel plasma concentration and clinical response will be valuable in utilizing this novel AED.

Population pharmacokinetic-pharmacodynamic analysis for eribulin mesilate-associated neutropenia.

AIMS: Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late-stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic-pharmacodynamic model for eribulin-associated neutropenia. METHODS: A combined data set of 12 phase I, II and III studies for eribulin mesilate was analysed. The population pharmacokinetics of eribulin was described using a previously developed model. The relationship between eribulin pharmacokinetic and neutropenia was described using a semi-physiological lifespan model for haematological toxicity. Patient characteristics predictive of increased sensitivity to develop neutropenia were evaluated using a simulation framework. RESULTS: Absolute neutrophil counts were available from 1579 patients. In the final covariate model, the baseline neutrophil count (ANC0) was estimated to be 4.03 × 10(9) neutrophils l(-1) [relative standard error (RSE) 1.2%], with interindividual variability (IIV, 37.3 coefficient of variation % [CV%]). The mean transition time was estimated to be 109 h (RSE 1.8%, IIV 13.9CV%), the feedback constant (γ) was estimated to be 0.216 (RSE 1.4%, IIV 12.2CV%), and the linear drug effect coefficient (SLOPE) was estimated to be 0.0451 µg l(-1) (RSE 3.2%, IIV 54CV%). Albumin, aspartate transaminase and receival of granulocyte colony-stimulating factor (G-CSF) were identified as significant covariates on SLOPE, and albumin, bilirubin, G-CSF, alkaline phosphatase and lactate dehydrogenase were identified as significant covariates on mean transition time. CONCLUSIONS: The developed model can be applied to investigate optimal treatment strategies quantitatively across different patient groups with respect to neutropenia. Albumin was identified as the most clinically important covariate predictive of interindividual variability in the neutropenia time course.

Exposure-Response Analyses of Polysomnography and Subjective Sleep Efficacy End Points From the Phase 3 Trials of Lemborexant, a Dual Orexin Receptor Antagonist for the Treatment of Insomnia.

This report describes polysomnography and sleep diary exposure-response analyses from Study E2006-G000-304 (Study 304), a 1-month trial of 5- or 10-mg lemborexant, zolpidem, or placebo; and Study E2006-G000-303 (Study 303), a 6-month trial of 5- or 10-mg lemborexant or placebo. Studies 304 and 303 included 1006 (86%) and 956 (68%) (female) participants, respectively; >40% were ≥65 years, with individual lemborexant exposures derived from a previously described pharmacokinetic model. Linear mixed-effects analyses of polysomnography: latency to persistent sleep (LPS), sleep efficiency (SE), and wake after sleep onset (WASO) quantified the change from baseline given lemborexant exposure, time, and covariates, guided by consensus recommendations regarding clinical significance. A small impact of sex, body weight, and race was predicted for LPS and SE, irrespective of treatment. Effect of age on LPS was small; baseline SE was estimated to be 8% higher for a 50-year-old versus an 80-year-old, decreasing to 6% by 1 month. Baseline WASO was 13 minutes longer for Black versus White subjects, corresponding to a 5-minute lower change from baseline at the end of the study. For subjective end points, the statistically significant covariate effects for age, sex, and race were not deemed therapeutically relevant, likely reflecting physiologic sleep pattern changes across age and study subgroups. Both polysomnography and subjective analyses indicated clinically meaningful differences from baseline for both lemborexant treatments, with effects being greater for 10-mg versus 5-mg lemborexant, while indicating that covariate-specific lemborexant dose adjustments are not warranted.

Post-Operative Medium- and Long-Term Endocrine Outcomes in Patients with Non-Functioning Pituitary Adenomas-Machine Learning Analysis.

Post-operative endocrine outcomes in patients with non-functioning pituitary adenoma (NFPA) are variable. The aim of this study was to use machine learning (ML) models to better predict medium- and long-term post-operative hypopituitarism in patients with NFPAs. We included data from 383 patients who underwent surgery with or without radiotherapy for NFPAs, with a follow-up period between 6 months and 15 years. ML models, including k-nearest neighbour (KNN), support vector machine (SVM), and decision tree models, showed a superior ability to predict panhypopituitarism compared with non-parametric statistical modelling (mean accuracy: 0.89; mean AUC-ROC: 0.79), with SVM achieving the highest performance (mean accuracy: 0.94; mean AUC-ROC: 0.88). Pre-operative endocrine function was the strongest feature for predicting panhypopituitarism within 1 year post-operatively, while endocrine outcomes at 1 year post-operatively supported strong predictions of panhypopituitarism at 5 and 10 years post-operatively. Other features found to contribute to panhypopituitarism prediction were age, volume of tumour, and the use of radiotherapy. In conclusion, our study demonstrates that ML models show potential in predicting post-operative panhypopituitarism in the medium and long term in patients with NFPM. Future work will include incorporating additional, more granular data, including imaging and operative video data, across multiple centres.

Non-functioning pituitary macroadenoma following surgery: long-term outcomes and development of an optimal follow-up strategy.

Objectives: Recurrence and regrowth of non-functioning pituitary macroadenomas (NFPMs) after surgery are common but remain unpredictable. Therefore, the optimal timing and frequency of follow-up imaging remain to be determined. We sought to determine the long-term surgical outcomes of NFPMs following surgery and develop an optimal follow-up strategy. Methods: Patients underwent surgery for NFPMs between 1987 and 2018, with a follow-up of 6 months or more, were identified. Demographics, presentation, management, histology, imaging, and surgical outcomes were retrospectively collected. Results: In total, 383 patients were included; 256 were men (256/383; 67%) with median follow-up of 8 years. Following primary surgery, 229 patients (229/383; 60%) achieved complete resection. Of those, 28 (28/229; 11%) developed recurrence, including six needed secondary surgery (6/229; 3%). The rate of complete resection improved over time; in the last quartile of cases, 77 achieved complete resection (77/95; 81%). Reoperation-free survival at 5, 10 and 15 years was 99%, 94% and 94%, respectively. NFPMs were incompletely resected in 154 patients (154/383; 40%); of those, 106 (106/154; 69%) had regrowth, and 84 (84/154; 55%) required reoperation. Surgical reintervention-free survival at 5, 10 and 15 years was 74%,49% and 35%, respectively. Young age and cavernous sinus invasion were risk factors for undergoing reoperation (P < 0.001 and P < 0.0001, respectively) and radiotherapy (P = 0.003 and P < 0.001, respectively). Patients with residual tumour required reoperation earlier than those underwent complete resection (P = 0.02). Radiotherapy to control tumour regrowth was delivered to 65 patients (65/383; 17%) after median time of 1 year following surgery. Radiotherapy was administered more in patients with regrowth of residual disease (61/106; 58%) than those who had NFPMs recurrence (4/28; 14%) (P ≤ 0.001) Following postoperative radiotherapy, one patient (1/65; 2%) had evidence of regrowth, seven (7/65; 11%) had tumour regression on imaging, and no patients underwent further surgery. Conclusions: NFPMs recurrence and regrowth are common, particularly in patients with residual disease post-operatively. We propose a follow-up strategy based on stratifying patients as "low risk" if there is no residual tumour, with increasing scan intervals, or "high risk" if there is a residual tumour, with annual scans for at least five years and extended lifelong surveillance after that.

Pituitary function at presentation and following therapy in patients with non-functional pituitary macroadenomas: a single centre retrospective cohort study.

BACKGROUND: Non-functioning pituitary macroadenomas (NFPMs) may present with hypopituitarism. Pituitary surgery and radiotherapy pose an additional risk to pituitary function. OBJECTIVES: To assess the incidence of hypopituitarism at presentation, the impact of treatment, and the likelihood of endocrine recovery during follow-up. METHODS: All patients treated surgically with and without radiotherapy for NFPMs between 1987 and 2018 who had longer than six months follow-up were identified. Demographics, presentation, investigation, treatment, and outcomes were collected. RESULTS: In total, 383 patients were identified. The median age was 57 years, with a median follow-up of 8 years. Preoperatively, 227 patients (227/375; 61%) had evidence of at least one pituitary deficiency. Anterior panhypopituitarism was more common in men (p = 0.001) and older patients (p = 0.005). Multiple hormone deficiencies were associated with large tumours (p = 0.03). Patients treated with surgery and radiotherapy had a higher incidence of all individual pituitary hormone deficiency, anterior panhypopituitarism, and significantly lower GH, ACTH, and TSH deficiencies free survival probability than those treated with surgery alone. Recovery of central hypogonadism, hypothyroidism, and anterior panhypopituitarism was also less likely to be reported in those treated with surgery and radiotherapy. Those with preoperative hypopituitarism had a higher risk of pituitary impairment at latest review than those presented with normal pituitary function (p = 0.001). CONCLUSION: NFPMs are associated with a significant degree of hypopituitarism at time of diagnosis and post-therapy. The combination of surgery and radiotherapy is associated with a higher risk of pituitary dysfunction. Recovery of pituitary hormone deficit may occur after treatment. Patients should have regular ongoing endocrine evaluation post-treatment to assess changes in pituitary function and the need for long-term replacement therapy.

A combined physiologically-based pharmacokinetic and quantitative systems pharmacology model for modeling amyloid aggregation in Alzheimer's disease.

Antibody-mediated removal of aggregated ß-amyloid (Aß) is the current, most clinically advanced potential disease-modifying treatment approach for Alzheimer's disease. We describe a quantitative systems pharmacology (QSP) approach of the dynamics of Aß monomers, oligomers, protofibrils, and plaque using a detailed microscopic model of Aß40 and Aß42 aggregation and clearance of aggregated Aß by activated microglia cells, which is enhanced by the interaction of antibody-bound Aß. The model allows for the prediction of Aß positron emission tomography (PET) imaging load as measured by a standardized uptake value ratio. A physiology-based pharmacokinetic model is seamlessly integrated to describe target exposure of monoclonal antibodies and simulate dynamics of cerebrospinal fluid (CSF) and plasma biomarkers, including CSF Aß42 and plasma Aß42 /Aß40 ratio biomarkers. Apolipoprotein E genotype is implemented as a difference in microglia clearance. By incorporating antibody-bound, plaque-mediated macrophage activation in the perivascular compartment, the model also predicts the incidence of amyloid-related imaging abnormalities with edema (ARIA-E). The QSP platform is calibrated with pharmacological and clinical information on aducanumab, bapineuzumab, crenezumab, gantenerumab, lecanemab, and solanezumab, predicting adequately the change in PET imaging measured amyloid load and the changes in the plasma Aß42 /Aß40 ratio while slightly overestimating the change in CSF Aß42 . ARIA-E is well predicted for all antibodies except bapineuzumab. This QSP model could support the clinical trial design of different amyloid-modulating interventions, define optimal titration and maintenance schedules, and provide a first step to understand the variability of biomarker response in clinical practice.

First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of E6742, a Dual Antagonist of Toll-like Receptors 7 and 8, in Healthy Volunteers.

The first-in-human phase I study for E6742, a dual toll-like receptor (TLR) 7 and TLR8 antagonist, has been conducted to assess the safety, tolerability, and pharmacokinetics of E6742 in healthy volunteers. In a single ascending dose (SAD) study, 42 subjects received 10-800 mg of E6742 in the fasted state, as well as a 100-mg cohort in the fed state for evaluating the effect of food. In a multiple ascending dose (MAD) study, 18 subjects received 100-400 mg of E6742 twice daily for 7 days. E6742 was rapidly absorbed with a median tmax ranging from 1.50 to 2.50 hours across dose groups under the fasted condition, and eliminated with a median t½ ranging from 2.37 to 14.4 hours. After multiple oral doses, a steady state was reached by day 7. In the SAD study, dose proportionality was observed for Cmax , AUC(0-t) , and AUC(0-inf) values of E6742 up to 800 mg, but these values were slightly less than dose proportional at 10 mg. In the MAD study, the Cmax and AUC(0-12h)ss of E6742 appeared to be almost dose proportionally increased between 100 and 200 mg, while these parameters showed more than a dose proportional increase at 400 mg. In addition to safety and good tolerability, this study demonstrated cytokine concentrations in cultured peripheral blood in response to E6742 were suppressed in a dose-dependent manner. Further clinical studies targeting systemic lupus erythematosus patients are currently underway.

Natural history of non-functioning pituitary microadenomas: results from the UK non-functioning pituitary adenoma consortium.

OBJECTIVE: The optimal approach to the surveillance of non-functioning pituitary microadenomas (micro-NFPAs) is not clearly established. Our aim was to generate evidence on the natural history of micro-NFPAs to support patient care. DESIGN: Multi-centre, retrospective, cohort study involving 23 endocrine departments (UK NFPA consortium). METHODS: Clinical, imaging, and hormonal data of micro-NFPA cases between January, 1, 2008 and December, 21, 2021 were analysed. RESULTS: Data for 459 patients were retrieved [median age at detection 44 years (IQR 31-57)-152 males/307 females]. Four hundred and nineteen patients had more than two magnetic resonance imagings (MRIs) [median imaging monitoring 3.5 years (IQR 1.71-6.1)]. One case developed apoplexy. Cumulative probability of micro-NFPA growth was 7.8% (95% CI, 4.9%-8.1%) and 14.5% (95% CI, 10.2%-18.8%) at 3 and 5 years, respectively, and of reduction 14.1% (95% CI, 10.4%-17.8%) and 21.3% (95% CI, 16.4%-26.2%) at 3 and 5 years, respectively. Median tumour enlargement was 2 mm (IQR 1-3) and 49% of micro-NFPAs that grew became macroadenomas (nearly all >5 mm at detection). Eight (1.9%) patients received surgery (only one had visual compromise with surgery required >3 years after micro-NFPA detection). Sex, age, and size at baseline were not predictors of enlargement/reduction. At the time of detection, 7.2%, 1.7%, and 1.5% patients had secondary hypogonadism, hypothyroidism, and hypoadrenalism, respectively. Two (0.6%) developed hypopituitarism during follow-up (after progression to macroadenoma). CONCLUSIONS: Probability of micro-NFPA growth is low, and the development of new hypopituitarism is rare. Delaying the first follow-up MRI to 3 years and avoiding hormonal re-evaluation in the absence of tumour growth or clinical manifestations is a safe approach for micro-NFPA surveillance.

Intravenous Perampanel as an Interchangeable Alternative to Oral Perampanel: A Randomized, Crossover, Phase I Pharmacokinetic and Safety Study.

Intravenous (IV) drug administration enables treatment of epilepsy when oral administration is temporarily not feasible. Perampanel is a once-daily antiseizure medication currently available as oral formulations. Study 050 (NCT03376997) was an open-label, randomized, single-dose, crossover study to evaluate the interchangeability of oral and IV perampanel in healthy subjects (N = 48). Bioequivalence of single 12-mg doses of IV (30-, 60-, or 90-minute infusion) and oral perampanel, ≥6 weeks apart, was assessed. Analyses indicated bioequivalence of area under the plasma concentration-time curve extrapolated to infinity for 30- and 60-minute IV infusions and oral perampanel doses (geometric mean ratio [90% confidence interval], 0.93 [0.84-1.02] and 1.03 [0.97-1.09], respectively); however, IV maximum observed drug concentration (Cmax ) values were 1.35- to 1.61-fold higher than Cmax . Simulated plasma concentration-time profiles using pooled pharmacokinetic data further supported oral and IV perampanel interchangeability in two scenarios: 12-mg per day IV dosing during a temporary 7-day switch from oral steady-state maintenance therapy, and treatment initiation with 2-mg perampanel. Thirty-four (70.8%) subjects experienced treatment-related adverse events. The IV perampanel safety profile was similar to that of oral perampanel without new safety concerns. Perampanel IV infusions may be a suitable temporary alternative to oral perampanel for treatment maintenance and/or initiation.